title: Centenarians as super-controls to assess the biological relevance of genetic risk factors for common age-related diseases: a proof of principle on type 2 diabetes.
abstract: Genetic association studies of age-related, chronic human diseases often suffer from a lack of power to detect modest effects. Here we propose an alternative approach of including healthy centenarians as a more homogeneous and extreme control group. As a proof of principle we focused on type 2 diabetes (T2D) and assessed /genotypic associations of 31 SNPs associated with T2D, diabetes complications and metabolic diseases and SNPs of genes relevant for telomere stability and age-related diseases. We hypothesized that the frequencies of risk variants are inversely correlated with decreasing health and longevity. We performed association analyses comparing diabetic patients and non-diabetic controls followed by association analyses with extreme phenotypic groups (T2D patients with complications and centenarians). Results drew attention to rs7903146 (TCF7L2 gene) that showed a constant increase in the frequencies of risk genotype (TT) from centenarians to diabetic patients who developed macro-complications and the strongest genotypic association was detected when diabetic patients were compared to centenarians (p_value = 9.066*10⁻⁷). We conclude that robust and biologically relevant associations can be obtained when extreme phenotypes, even with a small sample size, are compared.
authors.affiliation: DIMES - Department of Experimental, Diagnostic and Specialty Medicine, University of Bologna, Bologna, 40126 Italy. paolo.garagnani2@unibo.it
authors.forename: Paolo
authors.initials: P
authors.lastname: Garagnani
authors.forename: Cristina
authors.initials: C
authors.lastname: Giuliani
authors.forename: Chiara
authors.initials: C
authors.lastname: Pirazzini
authors.forename: Fabiola
authors.initials: F
authors.lastname: Olivieri
authors.forename: Maria Giulia
authors.initials: MG
authors.lastname: Bacalini
authors.forename: Rita
authors.initials: R
authors.lastname: Ostan
authors.forename: Daniela
authors.initials: D
authors.lastname: Mari
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Passarino
authors.forename: Daniela
authors.initials: D
authors.lastname: Monti
authors.forename: Anna Rita
authors.initials: AR
authors.lastname: Bonfigli
authors.forename: Massimo
authors.initials: M
authors.lastname: Boemi
authors.forename: Antonio
authors.initials: A
authors.lastname: Ceriello
authors.forename: Stefano
authors.initials: S
authors.lastname: Genovese
authors.forename: Federica
authors.initials: F
authors.lastname: Sevini
authors.forename: Donata
authors.initials: D
authors.lastname: Luiselli
authors.forename: Paolo
authors.initials: P
authors.lastname: Tieri
authors.forename: Miriam
authors.initials: M
authors.lastname: Capri
authors.forename: Stefano
authors.initials: S
authors.lastname: Salvioli
authors.forename: Jan
authors.initials: J
authors.lastname: Vijg
authors.forename: Yousin
authors.initials: Y
authors.lastname: Suh
authors.forename: Massimo
authors.initials: M
authors.lastname: Delledonne
authors.forename: Roberto
authors.initials: R
authors.lastname: Testa
authors.forename: Claudio
authors.initials: C
authors.lastname: Franceschi
mesh_terms: D000369:Aged, 80 and over; D000375:Aging / Q000235:genetics*; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics*; D005786:Gene Expression Regulation; D005787:Gene Frequency; D005819:Genetic Markers; D005838:Genotype; D006801:Humans; D020641:Polymorphism, Single Nucleotide; D012307:Risk Factors
chemical_list: D005819:Genetic Markers